Synaptic plasticity is widely regarded as the basis for learning, memory, and our ability to adapt to our surroundings. At the level of single neurons or at the level of human behavior, it is clear that plasticity is more robust when we are young. However there is untapped potential for plasticity, repair and regeneration in the adult mammalian brain, as evidenced by the birth of new neurons in several brain regions. These issues are central to the understanding and potential treatment of neurodevelopmental disorders, autism and mental retardation, as well as conditions that result in neural loss or degeneration such as stroke, epilepsy, brain and spinal cord trauma, Parkinson's disease, and Alzheimer's disease. The long-term goal of this project is to understand the mechanisms of circuit formation at the level of single synapses in the hippocampus. Much experimental effort has been directed at the very early period of neurogenesis, whereas much less is known about the integration of adult-generated neurons into functional networks in the adult brain. As for neural development, understanding the functional integration of new neurons in the adult is a daunting task because of the presumed contribution of hundreds of molecules in a spatially and temporally precise sequence. How does one approach this immense problem in the intact animal, yet gain access to single cells and synapses? This project makes use of a novel transgenic mouse to track the development of dendrites and synapses as new neurons leave their niche, and integrate into the adult circuitry of the dentate gyrus. Preliminary data suggests that this process occurs in distinct stages with a period of limited dendrite outgrowth and exclusively GABAergic synapses, followed weeks later by additional dendritic growth and new excitatory synapses. The project will use electrophysiology and cell imaging to chart the inputs and outputs as new neurons integrate into the adult network, both in normal conditions and following perturbations such as exercise and epileptic seizures. The role of molecules that regulate this stage-specific development will be tested using selective marking with specific promoters in transgenic mice, and viral-mediated gene manipulation in vivo. Assays will use biochemical and molecular methods as well as brain slice physiology. The ability to track these distinct stages will also be used to test the role of cell adhesion molecules in synapse maturation.Project Narrative Many neuropsychiatric illnesses cause loss of nerve cells and/or disruption of connections between nerve cells (synapses). This project takes advantage of a unique mouse model to examine the integration of adult- generated (new) neurons into synaptic networks in the hippocampus, thus providing access at the single nerve cell level to mechanisms of synapse formation, repair and regeneration in the brain. These issues are central to the understanding and potential treatment of neurodevelopmental disorders, autism, mental retardation and mood disorders, as well as conditions that result in neural loss or degeneration such as stroke, epilepsy, brain and spinal cord trauma, Parkinson's disease, and Alzheimer's disease.